2. MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS
Polymers of the peptide tubulin make up the microtubules that form the
microskeleton of cells. Additionally, during cell division these filaments
pull apart the nascent newly formed pair of nuclei. Compounds that interfere
with tubulin function and thus block this process have provided some valu-
able antitumor compounds. The vinca alkaloid drugs vincristine and vinblas-
tine, for example, block the self-assembly of tubulin into those filaments.
Paclitaxel, more familiarly known as Taxol, interestingly stabilizes tubulin
and in effect freezes cells into mid-division. Screening of marine natural
products uncovered the cytotoxic tripeptide-like compound hemiasterlin,
which owed its activity to inhibition of tubulin. A synthetic program
based on that lead led to the identification oftaltobulin( 69 ), an antitumor
compound composed, like its model, of sterically crowded aminoacid ana-
logues. The presence of the nucleophile-accepting acrylate moiety recalls 58.
One arm of the convergent synthesis begins with the construction of that
acrylate-containing moiety. Thus, condensation of thet-BOC protected
a-aminoaldehyde derived from valine with the carbethoxymethylene phos-
porane ( 60 ) gives the corresponding chain extended amino ester ( 61 ).
Exposure to acid serves to remove the protecting group to reveal the
primary amine ( 62 ). Condensation of that intermediate with the tertiary
butyl-substituted aminoacid 33 , used in a previous example leads to the
protected amide ( 63 ); thet-BOC group in this is again removed with
acid unmasking the primary amino group in 64. Construction of the
other major fragment first involves addition of a pair of methyl groups
- MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 11